eMedicine Specialties > Dermatology > Metabolic Diseases

Acrodermatitis Enteropathica

Kristina Marie Dela Rosa, MD, Flight Surgeon, Commander Naval Air Forces, NAS North Island
Elizabeth Kline Satter, MD, MPH, Chairman, Department of Dermatology, Naval Medical Center San Diego

Updated: Oct 30, 2009

Introduction

Background

Acrodermatitis enteropathica is a rare inherited form of zinc deficiency, characterized by periorificial and acral dermatitis, alopecia, and diarrhea.

Pathophysiology

Zinc is an essential trace nutrient required for the proper function of more than 100 enzymes and plays a crucial role in nucleic acid metabolism.^1,2

Acrodermatitis enteropathica is an autosomal recessive disorder postulated to occur as a result of mutations in the SLC39A4 gene located on band 8q24.3.^3,4,5 The SLC39A4 gene encodes a transmembrane protein that is part of the zinc/iron-regulated transporter–like protein (ZIP) family required for zinc uptake.⁶ This protein is highly expressed in the enterocytes in the duodenum and jejunum^7,8 ; therefore, affected individuals have a decreased ability to absorb zinc from dietary sources. Absence of a binding ligand needed to transport zinc may further contribute to zinc malabsorption.⁹

Differentiating acquired zinc deficiency disorders from acrodermatitis enteropathica is difficult because they have similar clinical presentations. Acquired zinc deficiency can occur as a result of low nutritional intake, malabsorption, excessive loss of zinc, or a combination of these factors.¹⁰ Acrodermatitis enteropathica can only be accurately diagnosed after attempts to remove zinc supplementation have failed.¹¹ Importantly, transient acquired zinc deficiencies can occur in premature infants secondary to their greater physiological demand for zinc and lower body stores.^12,13 Additionally, zinc deficiency can present in full-term breastfed infants as a result of low maternal serum zinc levels or a defect in mammary zinc secretion.¹ Thus, not all infants who have an acrodermatitis enteropathica–like presentation have the genetic disorder. Also see the Pediatrics article Acrodermatitis Enteropathica.

Frequency

United States

The frequency of acrodermatitis enteropathica is unknown.

International

An estimated 1 in 500,000 people in Denmark are affected by acrodermatitis enteropathica.¹⁴

Mortality/Morbidity

Without appropriate zinc supplementation, acrodermatitis enteropathica usually is lethal within the first few years of life. Untreated infants exhibit severe growth retardation, dermatitis, alopecia, secondary bacterial and fungal infections, and neurologic and behavioral changes; however, all symptoms are reversible with therapy.

Race

Acrodermatitis enteropathica has no racial predilection.

Sex

Acrodermatitis enteropathica has no sexual predilection.

Age

Acrodermatitis enteropathica typically appears in the first few weeks after birth if the child is fed bovine milk or shortly after cessation of breastfeeding.⁸ Acrodermatitis enteropathica can occur in children who are still breastfeeding if the levels of zinc are low in the breast milk.¹⁵

Clinical

History

Patients have a history of refractory diarrhea, failure to thrive, irritability, dermatitis, and alopecia that gradually appeared shortly after weaning from breast milk. Occasionally, patients have a history of siblings or other family members with similar symptoms in infancy.¹

Physical

• General: Infants are typically irritable and often inconsolable, and they show a slowing or cessation of growth and development.
• Skin: Erythematous, dry, and scaly patches and plaques are present and may evolve into crusted, vesiculobullous, erosive, psoriasiform, and pustular lesions. Lesions are predominantly distributed in a periorificial and acral pattern and may become secondarily infected with Staphylococcus aureus or Candida albicans.
• Mucosa: Findings include angular cheilitis, glossitis, conjunctivitis, blepharitis, punctate keratopathy, and photophobia.
• Nails: Paronychia and nail dystrophy are typical.
• Hair: Patients have loss of scalp hair, eyebrows, and eyelashes.

Sharply demarcated, brightly erythematous periorificial plaque in an infant with acrodermatitis enteropathica.

Causes

The etiopathogenesis of the zinc deficiency is postulated to occur as a result of a mutation in a zinc transport protein encoded by the SLC39A4 gene and perhaps alteration in a zinc transport ligand.¹⁶

Differential Diagnoses

Acquired zinc deficiency
Atopic Dermatitis
Candidiasis, Cutaneous
Candidiasis, Mucosal
Epidermolysis Bullosa
Seborrheic Dermatitis

Other Problems to Be Considered

Biotin and multiple decarboxylase deficiencies
Malabsorption syndromes secondary to cystic fibrosis or intestinal disease¹⁷
Essential fatty acid deficiencies
Kwashiorkor
Human immunodeficiency virus (HIV) disease
Iatrogenic deficiency of branched chain amino acids (isoleucine) in restrictive diets for maple syrup urine disease or methylmalonic aciduria¹⁸
Glutaric aciduria type 1¹⁹
Leucinosis
Nonketotic hyperglycinemia¹⁰

Workup

Laboratory Studies

Plasma zinc levels should be tested. Specimens should be collected in plastic syringes or acid-washed Vacutainer tubes with no rubber stopper to prevent exogenous contamination that could lead to spuriously normal measurements. Plasma zinc concentrations of less than 50 mcg/dL are suggestive, but not diagnostic, of acrodermatitis enteropathica.⁸

Hair, saliva, or urine zinc levels can be obtained but are rarely needed.²⁰

Because alkaline phosphatase is a zinc-dependent enzyme, reduced serum levels of alkaline phosphatase in the context of normal zinc levels can indicate a zinc deficiency.²¹ However, alkaline phosphatase levels are typically not decreased unless the individual has advanced disease.

Analysis of maternal breast milk zinc concentrations may help in differentiating acrodermatitis enteropathica from acquired zinc deficiency.¹

Histologic Findings

Light microscopy

Histological evaluation of a skin biopsy specimen is characteristic, but the same findings can be seen in other nutritional disorders. The histological findings vary with the age of the lesion. Early lesions show confluent parakeratosis associated with a reduced granular layer. Often, exocytosis of neutrophils into the epidermis is noted, which may be acanthotic and exhibit slight spongiosis. The intracellular edema eventuates into pallor of the upper third of the epidermis.²² Subsequently, subcorneal and intraepidermal clefts may develop as a result of massive ballooning and reticular degeneration, with necrosis of the keratinocytes.²³ In late lesions, psoriasiform hyperplasia of the epidermis and less epidermal pallor are noted.²⁴

Electron microscopy

Extracellular edema is associated with degenerate keratinocytes with multiple cytoplasmic vacuoles and slender, fingerlike protrusions. Few desmosomes are present, and the basal lamina is well preserved. Additionally, accumulation of cytoplasmic lipid droplets and intracellular edema in the spinous layer of the epidermis are seen.²⁵

Treatment

Medical Care

Treatment of acrodermatitis enteropathica requires lifelong zinc supplementation. Typically, 1-3 mg/kg of zinc gluconate or sulfate is administered orally each day.^8,12 Clinical improvement occurs prior to any significant change in the plasma zinc levels, usually within days to weeks of initiating treatment. Monitor serum zinc levels and alkaline phosphatase values every 3-6 months.⁸

Acrodermatitis enteropathica exacerbation during pregnancy or the stress of disease may require an increase in therapy.^{1 26}

Warm compresses to remove the scale crust, followed by application of white petrolatum to eroded skin lesions, may enhance reepithelialization when used concurrently with zinc replacement.

Diet

Although no special diet is required for acrodermatitis enteropathica patients, as long as zinc supplementation is continued, certain foods contain increased levels of zinc, including oysters, crab, beef, pork, and fowl. Zinc content is directly related to protein content.^14,27

Activity

No activity restrictions are necessary for acrodermatitis enteropathica patients.

Medication

Mineral supplements

These agents are used to reduce morbidity and to prevent complications in acrodermatitis enteropathica.

Zinc gluconate (Verazinc, Zinca-Pak, Orazinc)

One 10-mg tab contains 1.4 mg of elemental zinc.

Dosing

Adult

1 mg/kg/d PO for life

Pediatric

0.5-1 mg elemental zinc/kg PO qd, divided 1-3 times/d

Interactions

May reduce effect of penicillamine, tetracycline, and quinolones; concomitant administration of copper or iron with zinc may decrease their gastrointestinal absorption

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal impairment; very high dosages can result in sideroblastic anemia and microcytic anemia, secondary to zinc-induced copper deficiency (latter can be associated with neurologic defects)

Follow-up

Further Outpatient Care

Outpatient follow-up care is critical for acrodermatitis enteropathica patients to ensure proper growth and development.

Inpatient & Outpatient Medications

Zinc supplementation for acrodermatitis enteropathica is discussed in Medical Care.

Complications

If untreated, the lesions of acrodermatitis enteropathica may become secondarily infected with Staphylococcus aureus and Candida albicans. Additionally, high-dose zinc supplementation occasionally causes gastric upset and can adversely affect copper metabolism.²⁸

Prognosis

With zinc supplementation, the response rate is 100%; however, acrodermatitis enteropathica lead to death if not untreated.

Patient Education

In the future, genetic counseling with genetic testing may be available for siblings at risk for acrodermatitis enteropathica.

Miscellaneous

Medicolegal Pitfalls

Early diagnosis and treatment of acrodermatitis enteropathica should preclude any medicolegal pitfalls.

Multimedia

Media file 1: Sharply demarcated, brightly erythematous periorificial plaque in an infant with acrodermatitis enteropathica.

References

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2. Prasad AS. Zinc: an overview. Nutrition. Jan-Feb 1995;11(1 Suppl):93-9. [Medline].

3. Kury S, Dreno B, Bezieau S, et al. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat Genet. Jul 2002;31(3):239-40. [Medline].

4. Nakano A, Nakano H, Nomura K, Toyomaki Y, Hanada K. Novel SLC39A4 mutations in acrodermatitis enteropathica. J Invest Dermatol. Jun 2003;120(6):963-6. [Medline].

5. Wang K, Pugh EW, Griffen S, Doheny KF, Mostafa WZ, al-Aboosi MM. Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q24.3. Am J Hum Genet. Apr 2001;68(4):1055-60. [Medline].

6. Schmitt S, Kury S, Giraud M, Dreno B, Kharfi M, Bezieau S. An update on mutations of the SLC39A4 gene in acrodermatitis enteropathica. Hum Mutat. Jun 2009;30(6):926-33. [Medline].

7. Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am J Hum Genet. Jul 2002;71(1):66-73. [Medline].

8. Maverakis E, Fung MA, Lynch PJ, et al. Acrodermatitis enteropathica and an overview of zinc metabolism. J Am Acad Dermatol. Jan 2007;56(1):116-24. [Medline].

9. Evans GW, Johnson PE. Zinc-binding factor in acrodermatitis enteropathica. Lancet. Dec 11 1976;2(7998):1310. [Medline].

10. Samady JA, Schwartz RA, Shih LY, Piela Z, Lambert WC, Janniger CK. Acrodermatitis enteropathica-like eruption in an infant with nonketotic hyperglycinemia. J Dermatol. Sep 2000;27(9):604-8. [Medline].

11. Aggett PJ, Atherton DJ, More J, Davey J, Delves HT, Harries JT. Symptomatic zinc deficiency in a breast-fed preterm infant. Arch Dis Child. Jul 1980;55(7):547-50. [Medline].

12. Kiechl-Kohlendorfer U, Fink FM, Steichen-Gersdorf E. Transient symptomatic zinc deficiency in a breast-fed preterm infant. Pediatr Dermatol. Sep-Oct 2007;24(5):536-40. [Medline].

13. Connors TJ, Czarnecki DB, Haskett MI. Acquired zinc deficiency in a breast-fed premature infant. Arch Dermatol. Apr 1983;119(4):319-21. [Medline].

14. Champion RH, Burton JL, Ebling FJG. Textbook of Dermatology. 3. London: Blackwell Science; 1998:2668.

15. Roberts LJ, Shadwick CF, Bergstresser PR. Zinc deficiency in two full-term breast-fed infants. J Am Acad Dermatol. Feb 1987;16(2 Pt 1):301-4. [Medline].

16. Zimmerman AW, Hambidge KM, Lepow ML, Greenberg RD, Stover ML, Casey CE. Acrodermatitis in breast-fed premature infants: evidence for a defect of mammary zinc secretion. Pediatrics. Feb 1982;69(2):176-83. [Medline].

17. Schmidt CP, Tunnessen W. Cystic fibrosis presenting with periorificial dermatitis. J Am Acad Dermatol. Nov 1991;25(5 Pt 2):896-7. [Medline].

18. Tabanlioglu D, Ersoy-Evans S, Karaduman A. Acrodermatitis enteropathica-like eruption in metabolic disorders: acrodermatitis dysmetabolica is proposed as a better term. Pediatr Dermatol. Mar-Apr 2009;26(2):150-4. [Medline].

19. Niiyama S, Koelker S, Degen I, Hoffmann GF, Happle R, Hoffmann R. Acrodermatitis acidemica secondary to malnutrition in glutaric aciduria type I. Eur J Dermatol. May-Jun 2001;11(3):244-6. [Medline].

20. Van Wouwe JP. Clinical and laboratory diagnosis of acrodermatitis enteropathica. Eur J Pediatr. Oct 1989;149(1):2-8. [Medline].

21. Glover MT, Atherton DJ. Transient zinc deficiency in two full-term breast-fed siblings associated with low maternal breast milk zinc concentration. Pediatr Dermatol. Feb 1988;5(1):10-3. [Medline].

22. Gonzalez JR, Botet MV, Sanchez JL. The histopathology of acrodermatitis enteropathica. Am J Dermatopathol. Aug 1982;4(4):303-11. [Medline].

23. Mori H, Matsumoto Y, Tamada Y, Ohashi M. Apoptotic cell death in formation of vesicular skin lesions in patients with acquired zinc deficiency. J Cutan Pathol. Aug 1996;23(4):359-63. [Medline].

24. Jensen SL, McCuaig C, Zembowicz A, Hurt MA. Bullous lesions in acrodermatitis enteropathica delaying diagnosis of zinc deficiency: a report of two cases and review of the literature. J Cutan Pathol. Oct 2008;35 Suppl 1:1-13. [Medline].

25. Welsmann K, Kvist N, Kobayasi T. Bullous acrodermatitis due to zinc deficiency during total parenteral nutrition: an ultrastructural study of the epidermal changes. Acta Derm Venereol. 1983;63(2):143-6. [Medline].

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27. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganesse, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Available at http://ods.od.nih.gov/FactSheets/Zinc.asp#h3.. Accessed 9/9/09.

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Keywords

acrodermatitis enteropathica, AE, zinc deficiency, congenital zinc deficiency

Contributor Information and Disclosures

Author

Kristina Marie Dela Rosa, MD, Flight Surgeon, Commander Naval Air Forces, NAS North Island
Kristina Marie Dela Rosa, MD is a member of the following medical societies: American College of Physicians and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Elizabeth Kline Satter, MD, MPH, Chairman, Department of Dermatology, Naval Medical Center San Diego
Elizabeth Kline Satter, MD, MPH is a member of the following medical societies: Alpha Omega Alpha and American Medical Women's Association
Disclosure: Nothing to disclose.

Medical Editor

Eleanor E Sahn, MD, Director, Division of Pediatric Dermatology, Associate Professor, Departments of Dermatology and Pediatrics, Medical University of South Carolina
Eleanor E Sahn, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine
Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania
Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Timothy G. Woodall, MD, and previous Chief Editor, William D. James, MD, to the development and writing of this article.

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